EP1099706B1 - Sulphamates d'estrane comme inhibiteurs de sulfatase stéroidienne - Google Patents
Sulphamates d'estrane comme inhibiteurs de sulfatase stéroidienne Download PDFInfo
- Publication number
- EP1099706B1 EP1099706B1 EP00204525A EP00204525A EP1099706B1 EP 1099706 B1 EP1099706 B1 EP 1099706B1 EP 00204525 A EP00204525 A EP 00204525A EP 00204525 A EP00204525 A EP 00204525A EP 1099706 B1 EP1099706 B1 EP 1099706B1
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- European Patent Office
- Prior art keywords
- oestrone
- compound
- steroid sulphatase
- sulphamate
- sulphate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 0 CC(CC1)(C(CC2)C(CCc3c4)C1c3ccc4OS(N(C)*)(=O)=O)C2=O Chemical compound CC(CC1)(C(CC2)C(CCc3c4)C1c3ccc4OS(N(C)*)(=O)=O)C2=O 0.000 description 6
- DNXHEGUUPJUMQT-UHFFFAOYSA-N CC(CC1)(C(CC2)C(CCc3c4)C1c3ccc4O)C2=O Chemical compound CC(CC1)(C(CC2)C(CCc3c4)C1c3ccc4O)C2=O DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/32—Antioestrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/36—Antigestagens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
Definitions
- This invention relates to novel compounds for use as steroid sulphatase inhibitors, and pharmaceutical compositions containing them.
- Steroid precursors, or pro-hormones, having a sulphate group in the 3-position of the steroid nucleus are known to play an important part as intermediates in steroid metabolism in the human body.
- Oestrone sulphate and dehydroepiandrosterone (DHA) sulphate are known to play an important role as intermediates in the production, in the body, of oestrogens such as oestrone and oestradiol.
- Oestrone sulphate in particular, is known, for example, to represent one of the major circulating oestrogen precursors particularly in postmenopausal women and oestrone sulphatase activity in breast tumours is 100-1000 fold greater than that of other enzymes involved in oestrogen formation (James et al., Steroids, 50 , 269-279 (1987)).
- oestrogens such as oestrone and oestradiol, particularly the overproduction thereof, are strongly implicated in malignant conditions, such as breast cancer, see Breast Cancer, Treatment and Prognosis: Ed. R.A. Stoll, pp. 156-172, Blackwell Scientific Publications (1986), and the control of oestrogen production is the specific target of many anti-cancer therapies, both chemotherapy and surgical, e.g. oophorectomy and adrenalectomy. So far as endocrine therapy is concerned, efforts have so far tended to concentrate on aromatase inhibitors, i.e.
- Figure 1 shows, in the conversion of androgens such as androstenedione and testosterone to oestrone and oestradiol respectively.
- a first object of the present invention is to provide new compounds capable of inhibiting steroid sulphatase activity in vitro and in vivo.
- a second object of the present invention is to provide new compounds having improved activity as steroid sulphatase inhibitors both in vitro and in vivo.
- a third object of the invention is to provide pharmaceutical compositions effective in the treatment of oestrogen dependent tumours.
- a fourth object of the invention is to provide pharmaceutical compositions effective in the treatment of breast cancer.
- a fifth object of the invention is to provide a method for the treatment of oestrogen dependent tumours in mammals, especially humans.
- a sixth object of the invention is to provide a method for the treatment of breast cancer in mammals and especially in women.
- the invention is based on the discovery of novel compounds having steroid sulphatase inhibitory activity, in some cases, with extremely high activity levels.
- These compounds are the sulphamic acid esters of polycyclic alcohols, being polycyclic alcohols the sulphate of which is a substrate for enzymes having steroid sulphatase (EC 3.1.6.2) activity.
- the sulphamic acid esters of this invention are prepared by reacting the polycyclic alcohol, e.g. oestrone or dehydroepiandrosterone, with a sulphamoyl chloride R 1 R 2 NSO 2 Cl, i.e. the reaction scheme I
- the steroid sulphatase inhibitors of this invention can be formulated in any suitable manner utilising conventional pharmaceutical formulating techniques and pharmaceutical carriers, exipients, diluents etc. and usually for parenteral administration.
- Approximate effective dose rates are in the range 100 to 800 mg/day depending on the individual activities of the compounds in question and for a patient of average (70kg) bodyweight. More usual dosage rates for the preferred and more active compounds will be in the range 200 to 800 mg/day, more preferably, 200 to 500 mg/day, most preferably from 200 to 250 mg/day. They may be given in single dose regimes, split dose regimes and/or in multiple dose regimes lasting over several days.
- the compounds may be formulated in tablets, capsules, solution or suspension containing from 100 to 500 mg of compound per unit dose.
- the compounds will be formulated for parenteral administration in a suitable parenterally administrable carrier and providing single daily dosage rates in the range 200 to 800 mg, preferably 200 to 500, more preferably 200 to 250 mg.
- Such effective daily doses will, however, vary depending on inherent activity of the active ingredient and on the bodyweight of the patient, such variations being within the skill and judgement of the physician.
- the steroid sulphatase inhibitors of this invention may be used in combination therapies, either with another sulphatase inhibitor, or, for example, in combination with an aromatase inhibitor, such as for example, 4-hydroxyandrostenedione (4-OHA).
- an aromatase inhibitor such as for example, 4-hydroxyandrostenedione (4-OHA).
- reaction mixture was poured onto a cold saturated solution of sodium bicarbonate and the resulting aqueous phase was extracted with dichloromethane.
- the combined organic extracts were dried over anhydrous MgSO 4 . Filtration followed solvent evaporation in vacuo and co-evaporation with toluene afforded a crude residue which is further purified by flash chromatography.
- Example 1 The procedure of Example 1 was repeated save that sulphamoyl chloride was replaced by the same quantity of N-methylsulphamoyl chloride.
- Example 1 The procedure of Example 1 was repeated save that sulphamoyl chloride was replaced by the same quantity of N,N-dimethylsulphamoyl chloride.
- Steroid sulphatase is defined as: Steryl Sulphatase EC 3.1.6.2.
- Steroid sulphatase activity was measured in vitro using intact MCF-7 human breast cancer cells. This hormone dependent cell line is widely used to study the control of human breast cancer cell growth. It possesses significant steroid sulphatase activity (MacIndoe et al. Endocrinology, 123 , 1281-1287 (1988); Purohit & Reed, Int. J Cancer , 50 , 901-905 (1992)) and is available in the U.S.A. from the American Type Culture Collection (ATCC) and in the U.K. (e.g. from The Imperial Cancer Research Fund).
- ATCC American Type Culture Collection
- MEM Minimal Essential Medium
- HEPES Flow Laboratories, Irvine, Scotland
- 5% foetal bovine serum 20 mM HEPES
- 2 mM glutamine 2 mM glutamine
- non-essential amino acids 0.075% sodium bicarbonate.
- Up to 30 replicate 25 cm 2 tissue culture flasks were seeded with approximately 1 x 10 5 cells/flask using the above medium. Cells were grown to 80% confluency and medium was changed every third day.
- Intact monolayers of MCF-7 cells in triplicate 25 cm 2 tissue culture flasks were washed with Earle's Balanced Salt Solution (EBSS from ICN Flow, High Wycombe, U.K.) and incubated for 3-4 hours at 37°C with 5 pmol (7 x 10 5 dpm) [6,7- 3 H]oestrone-3-sulphate (specific activity 60 Ci/mmol from New England Nuclear, Boston, Mass., U.S.A.) in serum-free MEM (2.5 ml) together with oestrone-3-sulphamate (11 concentrations: 0; 1fM; 0.01pM; 0.1pM; 1pM; 0.01nM; 0.1nM; 1nM; 0.01 ⁇ M; 0.1 ⁇ M; 1 ⁇ M).
- EBSS Earle's Balanced Salt Solution
- the mass of oestrone-3-sulphate hydrolysed was calculated from the 3 H counts obtained (corrected for the volumes of the medium and organic phase used, and for recovery of [ 14 C]oestrone added) and the specific activity of the substrate.
- Each batch of experiments included incubations of microsomes prepared from a sulphatase-positive human placenta (positive control) and flasks without cells (to assess apparent non-enzymatic hydrolysis of the substrate).
- the number of cell nuclei per flask was determined using a Coulter Counter after treating the cell monolayers with Zaponin.
- One flask in each batch was used to assess cell membrane status and viability using the Trypan Blue exclusion method (Phillips, H.J. (1973) In: Tissue culture and applications , [eds: Kruse, D.F. & Patterson, M.K.]; pp. 406-408; Academic Press, New York).
- Results for steroid sulphatase activity are expressed as the mean ⁇ 1 S.D. of the total product (oestrone + oestradiol) formed during the incubation period (20 hours) calculated for 10 6 cells and, for values showing statistical significance, as a percentage reduction (inhibition) over incubations containing no oestrone-3-sulphamate. Unpaired Student's t-test was used to test the statistical significance of results.
- Steroid Sulphatase Activity in MCF-7 cells in the presence of Oestrone-3-sulphamate Oestrone-3-sumphamate concentration Steroid Sulphatase Activity ⁇ (fmol/20 hr/10 6 cells) % reduction over control (% inhibition) 0 (control) 319.7 ⁇ 18.5 - 1fM 353.3 ⁇ 39.0 - 0.01pM 362.3 ⁇ 21.2 - 0.lpM 330.7 ⁇ 17.8 - 1pM 321.8 ⁇ 6.2 - 0.01nM 265.1 ⁇ 11.0 17.2% 0.1nM 124.8 ⁇ 12.4 60.9% 1nM 16.49 ⁇ 4.7 95.0% 0.01 ⁇ M 3.92 ⁇ 0.4 98.8% 0.1 ⁇ M 2.53 ⁇ 1.1 99.2% 1 ⁇ M 1.68 ⁇ 0.7 99.5%
- Example 4 An identical experimental protocol to that described in Example 4 was used to generate results for oestrone-3-N,N-dimethylsulphamate except that incubations contained oestrone-3-N,N-dimethylsulphamate (5 concentrations: 0; 0.001 ⁇ M; 0.01 ⁇ M; 0.1 ⁇ M; 1 ⁇ M) in place of oestrone-3-sulphamate.
- Steroid Sulphatase Activity in MCF-7 cells in the presence of oestrone-3-N,N-dimethylsulphamate Oestrone-3-N,N-dimethylsulphamate concentration Steroid Sulphatase Activity ⁇ (fmol/20 hr/10 6 cells) % reduction over control (% inhibition) 0 (control) 82.63 ⁇ 3.6 - 0.001 ⁇ M 68.33 ⁇ 3.2 17.3% 0.01 ⁇ M 46.0 ⁇ 4.9 44.3% 0.1 ⁇ M 17.43 ⁇ 4.3 78.9% 1 ⁇ M 11.89 ⁇ 3.7 85.6%
- Example 4 A similar experimental protocol to that described in Example 4 was used to determine the effect of pre-treating MCF-7 cells with oestrone-3-sulphamate and oestrone-3-N,N-dimethylsulphamate respectively.
- Intact monolayers were initially incubated for 2 hours at 37°C with 0.1 ⁇ M oestrone-3-sulphamate, oestrone-3-N,N-dimethylsulphamate or medium alone (control). The medium bathing the cells was then removed by aspiration and cells were washed 3 times successively with 5 ml of medium on each occasion. The resultant 'washed' cells were then re-suspended and incubated for 3-4 hours at 37°C in medium containing 5 pmol (7 x 10 5 dpm) [6,7- 3 H]oestrone-3-sulphate. All other aspects were identical to those described in Examples 3 and 4.
- Incubations (1 ml) were carried out using a protein concentration of 100 ⁇ g/ml, substrate concentration of 20 ⁇ M [6,7- 3 H]oestrone-3-sulphate (specific activity 60 Ci/mmol from New England Nuclear, Boston, Mass., U.S.A.) and an incubation time of 20 minutes at 37°C.
- Eight concentrations of oestrone-3-sulphamate were employed: 0 (i.e. control); 0.05 ⁇ M; 0.1 ⁇ M; 0.2 ⁇ M; 0.4 ⁇ M; 0.6 ⁇ M; 0.8 ⁇ M; 1.0 ⁇ M.
- Results for oestrone-3-sulphamate are shown in Table IV and Figure 5.
- Results for steroid sulphatase activity are expressed in Table IV as total product (oestrone + oestradiol) formed during the incubation period (time) and as a percentage reduction (inhibition) over incubations containing no oestrone-3-sulphamate which acted as control.
- Results for steroid sulphatase activity are expressed in Figure 4 as percentage reduction (inhibition) over control against concentration of oestrone-3-sulphamate and include the calculated IC 50 value (i.e. the concentration of oestrone-3-sulphamate which produces 50% inhibition in relation to control) of 0.07 ⁇ M.
- Steroid Sulphatase Activity in placental microsomes in the presence of Oestrone-3-sulphamate Oestrone-3-sulphamate concentration Steroid Sulphatase Activity (pmol/hr/0.1 mg protein) % reduction over control (% inhibition) 0 (control) 768.6 - 0.05 ⁇ M 430.4 44.0% 0.1 ⁇ M 305.9 60.2% 0.2 ⁇ M 140.0 81.8% 0.4 ⁇ M 83.3 89.2% 0.6 ⁇ M 61.8 92.0% 0.8 ⁇ M 49.2 93.6% 1.0 ⁇ M 51.6 93.3%
- liver microsomal preparations were prepared by an identical protocol to that described in Example 6 except that the tissue source was rat liver and that duplicate experiments to determine steroid sulphatase activity were performed using [6,7- 3 H]oestrone-3-sulphate and [7- 3 H]dehydroepiandrosterone-3-sulphate as separate substrates.
- Results for steroid sulphatase activity are shown in Table V and are expressed as total product formed during the incubation period in the form of mean ⁇ 1 S.D. Results for incubations of tissue obtained from groups of rats treated with oestrone-3-sulphamate are also expressed as a percentage reduction (inhibition) in steroid sulphatase activity compared to their respective controls.
- Steroid Sulphatase Activity in Liver Microsome Preparations from Rats treated with subcutaneous Oestrone-3-sulphamate Treatment Group Assay Substrate Steroid Sulphatase Activity ⁇ (nmol/30 min/200 ⁇ g protein) % reduction over control control (vehicle) E 1 -SO 3 NH 2 E 1 -S E 1 -S 20.95 ⁇ 0.2 0.34 ⁇ 0.1 - 98.4% control (E 1 -S) E 1 -S + E 1 -SO 3 NH 2 E 1 -S E 1 -S 20.6 ⁇ 0.4 0.21 ⁇ 0.03 - 99.0% control (vehicle) E 1 -SO 3 NH 2 DHA-S DHA-S 1.73 ⁇ 0.4 0.1 ⁇ 0.01 - 94.2% control (E 1 -S) E 1 -S + E 1 -SO 3 NH 2 DHA-S DHA-S 1.71 ⁇ 0.1 0.09 ⁇ 0.01 -
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Claims (3)
- Procédé pour la préparation d'un composé sulfamate purifié, de formule dans laquelle R1 et R2 représentent des atomes de H ; et
dans laquelle le groupe polycycle est un résidu d'oestrone, d'oestradiol ou d'oestriol ;
dans laquelle le composé est un inhibiteur d'une enzyme ayant une activité de stéroïde-sulfatase (E.C.3.1.6.2) ;
dans laquelle si le groupe sulfamate sur le composé devait être remplacé par un groupe sulfate pour former un composé sulfate et mis en incubation avec une enzyme stéroïde-sulfatase (E.C.3.1.6.2) à un pH de 7,4 et une température de 37°C, il donnerait une valeur de Km inférieure à 50 µm,
le procédé comprenant la réaction d'oestrone, d'oestradiol ou d'oestriol avec un composé de sulfamatation correspondant au groupe sulfamate du composé sulfamate. - Procédé pour la préparation d'une composition pharmaceutique, procédé comprenant le mélange d'un support ou diluant pharmaceutiquement acceptable et d'un composé de formule dans laquelle R1 et R2 représentent des atomes de H ; et
dans laquelle le groupe polycycle est un résidu d'oestrone, d'oestradiol ou d'oestriol ;
dans laquelle le composé est un inhibiteur d'une enzyme ayant une activité de stéroïde-sulfatase (E.C.3.1.6.2) ;
si le groupe sulfamate sur le composé devait être remplacé par un groupe sulfate pour former un composé sulfate et mis en incubation avec une enzyme stéroïde-sulfatase (E.C.3.1.6.2) à un pH de 7,4 et une température de 37°C, il donnerait une valeur de Km inférieure à 50 µm. - Utilisation d'un composé dans la production d'un médicament destiné à inhiber une activité de stéroïde-sulfatase, dans laquelle le composé est un composé de formule dans laquelle R1 et R2 représentent des atomes de H ; et
dans laquelle le groupe polycycle est un résidu d'oestrone, d'oestradiol ou d'oestriol ;
dans laquelle le composé est un inhibiteur d'une enzyme ayant une activité de stéroide-sulfatase (E.C.3.1.6.2) ;
dans laquelle si le groupe sulfamate sur le composé devait être remplacé par un groupe sulfate pour former un composé sulfate et mis en incubation avec une enzyme stéroïde-sulfatase (E.C.3.1.6.2) à un pH de 7,4 et une température de 37°C, il donnerait une valeur de Km inférieure à 50 µm.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04077164A EP1522543A1 (fr) | 1991-08-29 | 1992-08-28 | Utilisation des inhibiteurs de steroidsulphatase pour la preparation d'un medicament pour la traitement des tumeurs dependent des estrogene |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9118478 | 1991-08-29 | ||
GB919118478A GB9118478D0 (en) | 1991-08-29 | 1991-08-29 | Steroid sulphatase inhibitors |
EP98204340A EP0921130B1 (fr) | 1991-08-29 | 1992-08-28 | Inhibiteurs de sulfatase stérodienne |
EP92918285A EP0641355B1 (fr) | 1991-08-29 | 1992-08-28 | usage des derivatives de sulphamate comme INHIBITEURS DE SULFATASE STEROIDIENNE |
Related Parent Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98204340A Division EP0921130B1 (fr) | 1991-08-29 | 1992-08-28 | Inhibiteurs de sulfatase stérodienne |
EP92918285.5 Division | 1993-03-22 | ||
EP98204340.8 Division | 1998-12-18 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP04077164A Division EP1522543A1 (fr) | 1991-08-29 | 1992-08-28 | Utilisation des inhibiteurs de steroidsulphatase pour la preparation d'un medicament pour la traitement des tumeurs dependent des estrogene |
EP04077164.4 Division-Into | 2004-07-27 |
Publications (3)
Publication Number | Publication Date |
---|---|
EP1099706A2 EP1099706A2 (fr) | 2001-05-16 |
EP1099706A3 EP1099706A3 (fr) | 2002-09-04 |
EP1099706B1 true EP1099706B1 (fr) | 2004-10-06 |
Family
ID=10700604
Family Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP04077164A Withdrawn EP1522543A1 (fr) | 1991-08-29 | 1992-08-28 | Utilisation des inhibiteurs de steroidsulphatase pour la preparation d'un medicament pour la traitement des tumeurs dependent des estrogene |
EP92918285A Expired - Lifetime EP0641355B1 (fr) | 1991-08-29 | 1992-08-28 | usage des derivatives de sulphamate comme INHIBITEURS DE SULFATASE STEROIDIENNE |
EP98204340A Expired - Lifetime EP0921130B1 (fr) | 1991-08-29 | 1992-08-28 | Inhibiteurs de sulfatase stérodienne |
EP98204337A Expired - Lifetime EP0928609B1 (fr) | 1991-08-29 | 1992-08-28 | Compositions pharmaceutique contenant des derivées de sulphamate comme inhibiteurs de sulfatase stéroide |
EP00204525A Expired - Lifetime EP1099706B1 (fr) | 1991-08-29 | 1992-08-28 | Sulphamates d'estrane comme inhibiteurs de sulfatase stéroidienne |
EP99203449A Expired - Lifetime EP0982032B1 (fr) | 1991-08-29 | 1992-08-28 | Application d'un composé sterol contenant un groupement ester de sulphamate pour obtenir un médicament pour le controle de la production des oestrogènes |
Family Applications Before (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP04077164A Withdrawn EP1522543A1 (fr) | 1991-08-29 | 1992-08-28 | Utilisation des inhibiteurs de steroidsulphatase pour la preparation d'un medicament pour la traitement des tumeurs dependent des estrogene |
EP92918285A Expired - Lifetime EP0641355B1 (fr) | 1991-08-29 | 1992-08-28 | usage des derivatives de sulphamate comme INHIBITEURS DE SULFATASE STEROIDIENNE |
EP98204340A Expired - Lifetime EP0921130B1 (fr) | 1991-08-29 | 1992-08-28 | Inhibiteurs de sulfatase stérodienne |
EP98204337A Expired - Lifetime EP0928609B1 (fr) | 1991-08-29 | 1992-08-28 | Compositions pharmaceutique contenant des derivées de sulphamate comme inhibiteurs de sulfatase stéroide |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99203449A Expired - Lifetime EP0982032B1 (fr) | 1991-08-29 | 1992-08-28 | Application d'un composé sterol contenant un groupement ester de sulphamate pour obtenir un médicament pour le controle de la production des oestrogènes |
Country Status (26)
Country | Link |
---|---|
US (3) | US5616574A (fr) |
EP (6) | EP1522543A1 (fr) |
JP (6) | JP3219408B2 (fr) |
KR (4) | KR100258396B1 (fr) |
AT (5) | ATE246706T1 (fr) |
AU (2) | AU689043B2 (fr) |
BR (1) | BR9206434A (fr) |
CA (4) | CA2114630C (fr) |
CY (4) | CY2253B1 (fr) |
CZ (1) | CZ295939B6 (fr) |
DE (5) | DE69233431T2 (fr) |
DK (4) | DK0921130T3 (fr) |
ES (4) | ES2196483T3 (fr) |
FI (5) | FI940903A (fr) |
GB (1) | GB9118478D0 (fr) |
GE (6) | GEP20022637B (fr) |
GR (1) | GR3034579T3 (fr) |
HK (3) | HK1020672A1 (fr) |
HU (1) | HUT66097A (fr) |
LV (1) | LV12618B (fr) |
NO (6) | NO307301B1 (fr) |
RU (4) | RU2207134C2 (fr) |
SG (7) | SG115508A1 (fr) |
SK (4) | SK282189B6 (fr) |
UA (4) | UA41875C2 (fr) |
WO (1) | WO1993005064A1 (fr) |
Families Citing this family (72)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6011024A (en) | 1991-08-28 | 2000-01-04 | Imperial College Of Science Technology & Medicine | Steroid sulphatase inhibitors |
GB9118478D0 (en) * | 1991-08-29 | 1991-10-16 | Imperial College | Steroid sulphatase inhibitors |
GB9604709D0 (en) * | 1996-03-05 | 1996-05-01 | Imperial College | A compound |
US6476011B1 (en) | 1991-08-28 | 2002-11-05 | Sterix Limited | Methods for introducing an estrogenic compound |
GB9603325D0 (en) * | 1996-02-16 | 1996-04-17 | Imperial College | A compound |
GB9625334D0 (en) * | 1996-12-05 | 1997-01-22 | Imperial College | Compound |
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